The present invention relates generally to materials for biomedical application and more specifically to nonthrombogenic biomaterials having an enhanced affinity toward albumin.
In the application, implementation and implantation of biomaterials in bodily tissues, the problem of biocompatibility and biofunctionality of these materials has been the subject of extensive investigation. In particular those biomaterials which are intended to contact body tissues over a long period of time present various problems associated with physiological and chemical stability and compatability with respect to various contacted tissues.
Both bulk and surface properties determine the functional biocompatibility of the material. Mechanical strength, elasticity, flexibility, creep and fatigue resistance, chemical inertness, impermeability to water vapor, resistance to acid attack, etc. are desired bulk properties of many biomaterials which should be maintained in vivo. The surfaces of exogenous materials in contact with bodily tissues should desirably exhibit resistance to red and white thrombus formation (e.g. blood coagulation, platelet adhesion and aggregation) immunological attack, cell adhesion, pannus formation, etc. Thrombogenesis, embolization, pannus formation, etc. resulting from blood and other tissue interacting with the surface may compromise the intended use of the biomaterial in certain medical devices, and quite possibly result in device failure.
Application of most non-physiologic biomaterials and protheses to tissue contact initiates a series of physiologic events on the surface of such biomaterials. In particular, a biomaterial such as a synthetic polymer in contact with blood rapidly forms an adsorbed protein layer. Within seconds after application, the biomaterial interface is coated with a thin proteinaceous film, rich in fibrinogen, fibronectin and gamma globulin. As blood circulates, further protein components contribute to the thickness of the film. Conformational alterations and complexing of proteins occur, activating defense mechanisms, e.g. coagulation, platelet adhesion and aggregation, white cell adhesion, etc.
A number of approaches to provide tissue compatibility and specifically blood thromboresistance have been proposed and many promising materials have been developed. However none of the biomaterials developed heretofore have been totally successful and most have provided a poor compromise between device function and long term compatibility.
One such approach has been to modify the surface of existing biomaterials in an effort to prevent endogenous protein adhesion and accumulation so as to avoid coagulation and cell adhesion. Surface modification techniques which have been evaluated for biocompatibility and functionality include low polarity surfaces, negatively charged surfaces, and surfaces coated with biological material, e.g. enzymes, endothelial cells, and proteins.
The low polarity surfaces such as silicone polymers, and hydrogels, were developed in the view that low surface free energy, specifically low interfacial energy would limit the driving potential for adhesion of proteins and cellular material. Although the silicone biomaterials are substantially chemically inert and improve blood compatibility, platelet aggregation and cell accumulation eventually result with blood contact, especially at low blood flow rates.
Another approach to enhance thromboresistance was to provide materials having negatively charged surfaces. Electrets, hydrogels and negatively charged biological molecules such as heparin, exhibit this property and appear to have improved, but not provide complete thromboresistance. Hydrogels, water saturated polymeric gels exhibiting a net negative surface charge, offer high biological compatibility but by their very nature of high water content lack structural strength and durability.
The biological coated polymers are of considerable interest due to their variability and complexity. Proteinaceous material such as heparin, albumin, and streptokinase have all been covalently bound to polymeric surfaces to enhance thromboresistance. Albumin is of particular interest for a surface coating because of its apparent passivating activity.
Heretofore, albumin has been physically adsorbed, and electrostatically and covalently bound to polymer surfaces. While temporary and partial protection against thrombogenesis is obtained by these methods, the albumin coating is eventually denatured or lost. The loss of albumin functionality when passively adsorbed may be traced to competitive reactions with other proteins having higher affinities for the polymer surface, ablation of the adsorbed albumin, or conformational changes, and fragmentation. Furthermore covalently bound albumin is subject to internal masking by the polymer tertiary structure caused by long term reconstitution of the polymer surface. As the polymer undergoes tertiary reorganization new, unfilled binding sites are presented to which thrombogenic proteins may gain a "foothold".
It is therefore highly desirable to provide polymeric surfaces which are biocompatible and are functional over a long period of time. It is further desirable that these polymer surfaces provide consistent thromboresistance, resistance to cell adhesion in general and resistance to immunological attack over a range of blood flow rates including statis, pH, electrolyte conditions, and hematologic makeups such as anemia, polycythemia, and thrombocytemia.